23 rd CROI Report Back AETC/Community Consortium Harry W. Lampiris, MD Professor of Clinical Medicine, UCSF Chief, ID Section, Medical Service,

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1 23 rd CROI Report Back AETC/Community Consortium Harry W. Lampiris, MD Professor of Clinical Medicine, UCSF Chief, ID Section, Medical Service, SFVAMC March 23, 2016 Boston, MA, February 22-25, 2016

2 Disclosures I have no financial disclosures.

3 Outline Part 1 Initial ARV Therapy New Agents in Development Switch Studies Novel agents in development Part 2 Cure Research Update A few other interesting abstracts

4 Outline Part 1 Initial ARV Therapy New Agents in Development Switch Studies Novel agents in development Part 2 Cure Research Update A few other interesting abstracts

5 MK : Doravirine + TDF/FTC vs EFV + TDF/FTC In Treatment-Naive Pts Doravirine: investigational NNRTI with potent activity against common NNRTI resistance mutations, QD dosing, no PPI drug drug interactions, improved CNS safety vs EFV in early studies Minimal pheno resistance to viruses with K103N, Y181C, G190A RPV and EFV resistant viruses are sensitive to DOR and vice versa Gatell JM et al, CROI 2016, Abstract 470

6 MK : Doravirine + TDF/FTC vs EFV + TDF/FTC In Treatment-Naive Pts Gatell JM et al, CROI 2016, Abstract 470

7 Primary Endpoint: HIV RNA < 40 (ITT) Gatell JM et al, CROI 2016, Abstract 470

8 MK : Clinical Adverse Events Gatell JM, JM et et al. al, CROI CROI , Abstract Abstract 470. Reproduced 470 with permission.

9 MK : Conclusions Gatell JM et al, CROI 2016, Abstract 470

10 Study 1089: Switch from F/TDF to F/TAF at Week 48 Study Design Randomized, double-blind, double-dummy, activecontrolled study F/TAF QD Virologically Suppressed (< 50 c/ml) F/TDF + Third Agent egfr 50 ml/min n=333 F/TDF Placebo QD Continue Third Agent F/TDF QD n=330 F/TAF Dose: 200/10 mg with boosted PIs 200/25 mg with unboosted third agents Gallant J, et al. CROI Abstract 29 F/TAF Placebo QD Continue Third Agent BL Wk 48 Wk 96 Primary Endpoint Secondary HIV-1 RNA <50 c/ml Endpoint

11 Study 1089: Switch from F/TDF to F/TAF at Week 48 Baseline Characteristics F/TAF n=333 F/TDF n=330 Median age (range), years 48 (22, 78) 49 (22, 79) Female, n (%) 48 (14) 54 (16) Race, n (%) White 244 (73) 253 (77) Black or African descent 69 (21) 67 (20) Other 20 (6) 10 (3) Hispanic/Latino ethnicity, n (%) 48 (14) 78 (24) Median CD4 count, cells/mm <200 cells/mm 3, n (%) 5 (2) 4 (1) Median egfr *, ml/min Use of third agent, n (%) Boosted PI 155 (47) 150 (45) Unboosted third agents 178 (53) 180 (55) * egfr calculated with Cockcroft-Gault equation Gallant J, et al. CROI Abstract 29

12 HIV-1 RNA <50 c/ml, % Study 1089: Switch from F/TDF to F/TAF at Week 48 Efficacy at Week 48 (Snapshot) Virologic Outcome Treatment Difference (95% CI) F/TDF F/TAF Virologic Success Virologic Failure No Virologic Data 10% 0 +10% Gallant J, et al. CROI Abstract 29

13 HIV-1 RNA <50 c/ml, % Study 1089: Switch from F/TDF to F/TAF at Week 48 Virologic Success by Third Agent F/TAF (n=333) F/TDF (n=330) n, (%) Tested for Resistance* Resistance Mutation F/TAF 2 1 (0.3%) M184V F/TDF 1 -- * Confirmed HIV-1 RNA 50 c/ml at any visit or unconfirmed >400 c/ml at endpoint or discontinuation Gallant J, et al. CROI Boston, MA. #29

14 Study 1089: Other findings Similar AE rates and discontinuations in both arms EGFR improved greater with TAF than with TDF (8.4 vs 2.8 mg/min) Four renal biomarkers improved with TAF vs worsening for TDF Spine and hip BMD improved with TAF vs remaining unchanged with TDF Increased BMD >3% greater in TAF arm than TDF arm (30% vs 17%) LDL rose more in TAF arm than in TDF arm Gallant J, et al. CROI Abstract 29

15 LATTE-2: Cabotegravir IM + Rilpivirine IM for Long-Acting Maintenance ART Multicenter, open-label phase IIb study Primary endpoints: HIV-1 RNA < 50 c/ml by FDA snapshot, PDVF, and safety at maintenance Wk 32 ART-naive HIVinfected pts with CD4+ cell count > 200 cells/mm 3 Induction Phase* Wk 16: RPV PO added CAB 30 mg PO QD + ABC/3TC Margolis DA, et al. CROI Abstract 31LB. Wk 20 Maintenance Phase Wk 32 primary analysis; Wk 1 dose selection Wk 96 CAB 400 mg IM + RPV 600 mg IM Q4W (n = 115) CAB 600 mg IM + RPV 900 mg IM Q8W (n = 115) (N = 309) CAB 30 mg PO + ABC/3TC PO QD (n = 56) *Pts with HIV-1 RNA < 50 c/ml from Wk 16 to Wk 20 continued to maintenance phase. 6 pts discontinued for AEs or death in induction analysis. Margolis DA et al, CROI 2016, Abstract 31LB

16 HIV-1 RNA <50 c/ml (%) LATTE-2: Maintenance Wk 32 Virologic Efficacy (ITT-Maintenance Exposed) Virologic efficacy of Q4W and Q8W IM regimens similar to oral regimen No INSTI, NNRTI, or NRTI resistance mutations detected Virologic Success IM CAB + RPV Q4W (n = 115) IM CAB + RPV Q8W (n = 115) Oral CAB + ABC/3TC (n = 56) < < 1 5 Virologic Nonresponse No Virologic Data Treatment Differences (95% CI) Oral -4.8 Q8W IM Q4W Margolis DA, et al. CROI Abstract 31LB. Reproduced with permission. Margolis DA et al, CROI 2016, Abstract 31LB

17 LATTE-2: Safety data through wk 32 Most frequent ISRs were pain (67%), swelling (7%), and nodules (6%) AEs, % ISR events/injection: % of ISRs grade 1/2; none grade 4 Proportion of pts reporting ISRs decreased with time from 86% on Day 1 to 33% at Wk 32; 1% of pts withdrew for ISRs Pooled CAB + RPV IM Arms (n = 230) Oral CAB + ABC/3TC (n = 56) Drug-related grade 3/4 AEs (excluding ISRs) 3 0 Serious AEs 6 5 AEs leading to withdrawal 3 2 Margolis DA et al, CROI 2016, Abstract 31LB

18 Pts (%) LATTE-2: Wk 32 Pt Satisfaction With Maintenance Therapy vs Oral Induction How satisfied are you with your current treatment? How satisfied would you be to continue with your present form of treatment? More Neutral Less More Neutral Less Q8W (n = 106) Q4W (n = 100) Oral CAB (n = 49) Q8W (n = 106) Q4W (n = 100) Oral CAB (n = 49) Margolis DA, et al. CROI Abstract 31LB. Reproduced with permission. Margolis DA et al, CROI 2016, Abstract 31LB

19 Unique mechanism: RT translocation inhibitor Grobler JA et al, CROI 2016, Abstract 98

20 Friedman E et al., CROI 2016, Abstract 437 LB

21 Krystal M et al, CROI 2016, Abstract 97

22 Krystal M et al, CROI 2016, Abstract 97

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24 Outline Part 1 Initial ARV Therapy New Agents in Development Switch Studies Novel agents in development Part 2 Cure Research Update A few other interesting abstracts

25 Kick and Kill Strategy to Eliminate Reservoirs of Latent HIV KICK Activate expression of HIV KILL Kills cells expressing HIV proteins Latency Reversal Agents HDACis PKC agonists TLR7 agonists PROTECT cart Latent reservoir elimination Latent reservoir (rcd4 T cells) Immune effector cells Killing Strategies Therapeutic vaccines Anti-Env antibodies Anti-PD-L1 CD8 cells NK cells MΦs

26 Reduc Study: Vacc 4x + GMCSF (kill) & HDAC romidepsin (kick) 20 HIV+ pts, well controlled, received 6 sequential IM doses of Vacc 4x vaccine (4 gag epitopes) + GMCSF (adjuvant) followed by romedepsin IV infusions weekly x 3 Romidepsin previously approved for T cell lymphoma Results: 8/20 measureable HIV RNA; median HIV DNA reduction 40%; no reduction integrated HIV DNA S Leth et al, CROI 2016, Abstract 26 LB

27 Antilatency agent: αpd1-l1 (BMS ) Background: PD1 receptor upregulated in T cells that are exhausted αpd1-l1 and αpd1-l2 restore T cell function in vitro CD4+ latently infected cells express PD1 αpd1 decreases viral latency in vitro BMS agent caused retinal toxicity in animal studies Eron J et al., CROI 2016, Abstract 25

28 BMS : pilot study Results: Administered IV (0.3 mg/kg) to 6 HIV + patients on suppressive ARV vs placebo in 2 patients 2/6 recipients developed increased gag-specific CD8 T cell responses 1 recipient with 30 fold reduction cell-associated HIV RNA/DNA ratio One patient developed autoimmune hypophysitis (adrenal, gonadal insufficiency) 9 months post infusion Future studies with related agent (pembrolizumab) in HIV + patients with malignancy planned Eron J et al., CROI 2016, Abstract 25

29 ACTG 5340: VRC-01 Broadly Neutralizing Antibody (bnab) Targets CD4 binding site Study design: 40 mg/kg IV q3w x 3 doses in 14 pts in PI-or INI based ART suppressed x 6 mos d/c ARVs one week after first infusion Results: Modest delay virologic rebound in recipients (38% remained suppressed at week 4 after rx vs 13% in prior studies of treatment interruption); no difference at week 8?role for combination bnabs in future? Bar K et al., CROI 2016, Abstract 32LB

30 TLR-7 Agonists GS986 and GS9620 Background: TLR-7 increases antigen presentation, enhances activity of NK cells, B cells, CD4 and CD8 T cells Study design: 11 macaques infected with SIV and treated with TDF/FTC/DOL 65 days after infection Multiple doses GS6 and GS9620 given SC q 2w x 5 6 mos while receiving ARVs Results: Induces transient SIV viremia decreased proviral DNA in PBMCs, colon, LN bx ART discontinued and 2/9 macaques remain SIV RNA negative after 3 4 months Planned Phase 1b trial for HIV+ patients Whitney JB et al, CROI 2016, Abstract 95LB

31 Second Berlin Patient (from Dusseldorf)? 41 yo man with HIV (HIV RNA suppressed) underwent induction chemo 1/11 then allogeneic SCT 2/13 for relapse from CCR5Δ32 homozygote Proviral DNA 29K at baseline, R5 virus After SCT, multiple neg proviral DNA results from PBMC, rectal bx, BM bx, in 2 labs up to 2 years Kobbe G et al, CROI 2016, Abstract 364

32 Paroxitene + fluconazole for HAND? Background: HAND increases CNS inflammation, macrophage activation, oxidative stress PRX and FLUC neuroprotective in macaques Study Design single center study from Johns Hopkins: 45 patients with HIV on stable ARVs with low baseline NC function randomized to 4 treatment arms: PRX 20 mg qd; FLUC 100 mg q12; PRX + FLUC; placebo Analysis of 24 patients with >90% adherence after 6 mos Results: Improved NC scores on 8 neuropsych tests in PRX vs non PRX arms Sacktor N et al., CROI 2016, Abstract 146

33 ACTG 5298: Phase 3 RCT Quadrivalent HPV Vaccine HIV positive; age > 27 N = 575, 82% male, 18% women, mean CD4 602, HIV PCR < 50 in 83% Baseline anal and oral HPV, cytology, HRA Intervention: vaccine vs placebo week 0, 8, 24 Measurements: q6mos anal HPV, cytology, oral HPV Primary endpoint: persistent anal HPV Wilkin TJ et al, CROI 2016, Abstract 161

34 ACTG 5298: Phase 3 RCT Quadrivalent HPV Vaccine Results: DSMB terminated trial for futility 9/3/2015, median 2.6 years f/u No reduction in persistent anal HPV and HSIL Trend for reduction in persistent oral HPV in treatment arm Vaccine was safe and highly immunogenic Low infection rates and low persistence rates may explain negative results Wilkin TJ et al, CROI 2016, Abstract 161

35 Wilkin TJ et al, CROI 2016, Abstract 161

36 Wilkin TJ et al, CROI 2016, Abstract 161

37 Thank you Claire Rappoport Amanda Newstetter and AETC Staff Annie Luetkemeyer & Jackie Tulsky Gilead Sciences slides and sponsorship Clinical care options